








key: cord-332348-yi85sfks
authors: Liang, Yujie; Xu, Jiabin; Chu, Mei; Mai, Jianbo; Lai, Niangmei; Tang, Wen; Yang, Tuanjie; Zhang, Sien; Guan, Chenyu; Zhong, Fan; Yang, Liuping; Liao, Guiqing
title: Neurosensory dysfunction: a diagnostic marker of early COVID-19
date: 2020-06-29
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.06.086
sha: 
doc_id: 332348
cord_uid: yi85sfks

Abstract Objectives To detailly described the neurosensory dysfunction, including hyposmia, hypogeusia and tinnitus, in patients with COVID-19. Methods Clinical characteristics and oropharyngeal swabs were obtained from 86 patients with COVID-19 hospitalized in Guangzhou Eighth People’s Hospital. Chronological analysis method was used to detailly clarify the neurosensory dysfunction. The cycle threshold (Ct) values were used to approximately indicate viral load. Results Forth-four (51.2%) patients had neurosensory dysfunction: hyposmia (34, 39.5%), hypogeusia (33, 38.4%), and tinnitus (3, 3.5%). Neurosensory dysfunction was significantly more common in patients under 40 years old (p = 0.001) or women (p = 0.006). Hyposmia and hypogeusia coexisted in 23 (26.7%) patients. The interval between onset of hyposmia and hypogeusia was 0.7 ± 1.46 days. The interval from onset of hyposmia and hypogeusia to typical symptoms was 0.22 ± 4.57 and 0.75 ± 6.77 days; the interval from onset of hyposmia and hypogeusia to admission was 6.06 ± 6.68 and 5.76 ± 7.68 days; and the duration of hyposmia and hypogeusia was 9.09 ± 5.74 and 7.12 ± 4.66 days, respectively. The viral load was high since symptoms onset, peaked within the first week, and then gradually declined. Conclusions The neurosensory dysfunction tends to occur in the early stage of COVID-19, and it could be used as a marker for early diagnosis of COVID-19.

A global pandemic named Coronavirus Disease 2019 , caused by SARS-CoV-2 infection, has been wreaking havoc with the health of much of human civilization. By April 30, 2020, a total of more than 3 million patients with had been confirmed worldwide, including over 217 thousand deaths [1] .

Early diagnosis is key to the management of the COVID-19 pandemic. Recently, some researchers have reported that patients with COVID-19 would suffer from neurosensory dysfunction, including loss of smell (hyposmia) and taste (hypogeusia), with a prevalence of 5.1%-98% [2] [3] [4] [5] for hyposmia, and 5.6%-90.3% [2, 4, 5] for J o u r n a l P r e -p r o o f hypogeusia. However, the exact onset time and the duration of hyposmia and hypogeusia are rare reported.

Neurosensory dysfunction of patients with COVID-19 might be considered less harmful than typical symptoms (fever, cough, or shortness of breath) [6] . However, that did not mean it should be neglected. To clarify the onset time and duration of these symptoms will offer help for early diagnosis and accurate management of In this study, we report the characteristic neurosensory dysfunction in 44 of 86 patients with COVID-19. We detailly clarified the exact time of onset and duration of neurosensory dysfunction, using the chronological analysis method. The viral load of oropharyngeal swab tests was analyzed.

Eighty-six confirmed cases of COVID-19 (admission date from March 16 to April 12, 2020) at Guangzhou Eighth People's Hospital in Guangdong, China, which was the designated hospital exclusively for COVID-19 in Guangzhou, were included in this study. The confirmed criteria followed the latest Diagnosis and Treatment Guidelines for COVID-19 that issued by the National Health Committee of the People's Republic of China [7] . This study was performed in accordance to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Guangzhou Eighth People's Hospital. Verbal consent was obtained from patients before the enrollment.

Demographic information, clinical characteristics (included medical history, comorbidities, signs and symptoms), and laboratory findings were obtained from the J o u r n a l P r e -p r o o f electronic medical record system of Guangzhou Eighth People's Hospital and analyzed by three independent researchers. Neurosensory symptoms were obtained at the day of discharge using self-made questionnaire. The onset date was defined as the day when any symptoms were noticed by the patients. The method of chronology (A chronology is an account or record of the times and the order in which a series of past events took place) was used for analysis.

Oropharyngeal swabs were collected and placed into a sterile tube containing RNA preservation solution. The swabs were sent for SARS-CoV-2 RNA extraction and detection within 1 hour by a real-time reverse transcriptional polymerase chain reaction (RT-PCR )system by following the commercial test kit instructions (Da'an Gene cooperation, Cat DA0930) as previously described [8] . Briefly, two PCR primer and probe sets targeting ORF1a/b and nCoV-N genes were separately added into the same reaction tube. Positive and negative controls were involved for detection. Cycle threshold (Ct) values were used to quantify the viral load, with lower values indicating higher viral load. The samples were defined as viral positive when either or both genes of Ct value < 41.

Continuous variables were described as medians and range values. The analyses were carried out using GraphPad Prism 9 or IBM SPSS Statistics 25. Categorical variables were compared using the Fisher's exact test and continuous variables with the Mann-Whitney U test. Spearman's correlation test was performed to analysis relationship between age and viral load, as well as between days after symptom onset and test values.

The significant level was set as 0.05.

shown in Table 1 . The median age of patients was 25.5 years (range 6-57). 85 patients were with mild COVID-19 and 1 was severe case. 18 (20.9%) patients had at least one comorbidity: chronic liver diseases (8, 9 .3%), hyperlipidemia (3, 3.5%), cardio cerebrovascular disease (3, 3.5%), followed by hypertension, anemia and hyperthyroidism (2, 2.3%). The most common typical symptom was cough (41, 47.7%), followed by fever (26, 30.2%), fatigue and pharyngalgia (16, 18 .6%), anorexia (15, 17 .4%), headache (12, 14 .0%), myalgia (8, 9 .3%), diarrhea (6, 7.0%), and vomiting (4, 4.7%); and 11 (12.8%) patients showed no typical symptoms.

Forty-four (51.2%) patients had neurosensory dysfunction: hyposmia (34, 39.5%), hypogeusia (33, 38.4%), and tinnitus (3, 3.5%). Table 2 showed the demographic characteristics and laboratory findings of 44 cases with neurosensory dysfunction.

Patients with neurosensory dysfunction was noticed to have a younger age (median 23.5 years vs 31.5 years, p=0.024). Of the 44 patients, 42 (95.5%) were under 40 years old (6-39 years old). Neurosensory dysfunction was significantly more common in patients under 40 years old (p=0.001). Women develop neurosensory dysfunction more common than men (p=0.006). There was no significant correlation between comorbidity and neurosensory dysfunction. No obvious differences in laboratory tests were noticed between patients with and without neurosensory dysfunction. A total of 407 oropharyngeal swabs were obtained from 86 hospitalized patients (mean 4.7 specimens per patient). SARS-CoV-2 RNA was undetectable in oropharyngeal swabs from 24 patients after admission. The results showed that the viral load peaked within the first week since symptoms onset and then gradually declined; a significant negative correlation was noticed between viral load and days after symptom onset (r 2 =0.1250, p<0.001; Figure 2A ). The first positive results (Ct value < 41) of oropharyngeal swabs after admission was used to evaluate the initial viral load. There was no significant difference in initial Ct values between patients with and without neurosensory dysfunction ( Figure 2B ). Age group ( Figure 2C ) and gender ( Figure 2D) had no significant effect on initial Ct values.

In this study, we detailly provided the exact time of onset and duration of neurosensory dysfunction, including hyposmia, hypogeusia and tinnitus, of patients with COVID-19. Patients under 40 years old, as well as women, seem to be more susceptible to neurosensory dysfunction. Hyposmia tends to cooccur with hypogeusia in the early stage of COVID-19, even before onset of typical symptoms.

Most of the reports about loss of smell and taste appears in countries outside East Asia, with the incidence rate of 54.2%-90.3% [3, 5, [9] [10] [11] . There are only two reports on [2] reported that hyposmia and hypogeusia accounted for 5.1% and 5.8% of hospitalized patients in Wuhan, China. In the study via telephone interview by Lee et al. [4] , anosmia or ageusia was observed in 15.3% patients in the early stage of COVID- 19 . In our cohort, 44 (51.2%) showed neurosensory dysfunction, a percentage much higher than that in the two studies. The reason for this inconsistency may be that most of the patients in our cohort were imported cases who were infected with the coronavirus abroad, and as Forster et al. [12] reported, the genotyping of the coronavirus may be different (potential mutations).

The present study is the first to use the chronological analysis method to detailly clarify the neurosensory dysfunction of patients with COVID-19. The neurosensory dysfunction tends to occur in the early stage of COVID-19, even before onset of typical symptoms. The first evidence was that of the 11 patients who had no typical symptoms, 9 reported neurosensory dysfunction. Secondly, the onset time of neurosensory dysfunction is close to or even earlier than that of typical symptoms. Thirdly, the average duration of hyposmia and hypogeusia in this cohort was 9.09±5.74 days and 7.12±4.66 days, which was nearer to that of 7.5±3.2 days reported in Spain [9] . At present, the epidemic in Guangzhou has entered the final stage, and all patients were admitted to our hospital for treatment on the day of confirmation. These facts indicate that the neurosensory dysfunction may be present before SARS-CoV-2 is detected in the oropharyngeal swab. All the above evidence fully shows that neurosensory dysfunction can be used as a diagnostic marker of early COVID-19. Thus, our findings suggest adding neurosensory symptoms to the routine screening list for COVID-19. The reasons why neurosensory dysfunction often occurs early are still unclear. The following two factors could be taken into consideration. Firstly, high viral load in the beginning of infection may concern the development of neurosensory dysfunction. Our data revealed that the viral load remained at a high level for a week since symptom onset, which coincided with the duration of neurosensory dysfunction. However, no difference was noted in viral load between patients with and without neurosensory dysfunction, suggesting that the effect of viral load on the development of neurosensory dysfunction varies. Secondly, oral cavity and nasal cavity are the main routes for SARS-CoV-2 invasion. Studies show that ACE2 could be expressed in tongue epithelial cells [13] and olfactory epithelial cells [14] . These facts might lead to the early occurrence of neurosensory dysfunction.

Interestingly, neurosensory dysfunction seems to affect more young patients than the elderly, which is consistent with a study by Lechien et al. [7] in Europe. This finding may corroborate Yan et al. [4] demonstrating that smell loss in Covid-19 may associate with a milder clinical course. We also noticed a correlation between gender and the development of neurosensory dysfunction. There are many differences between men and women in the immune response to SARS-CoV-2 infection and inflammatory diseases [15] , and women are less susceptible to viral infections based on a different innate immunity, steroid hormones and factors related to sex chromosomes [15] . A study by Suzuki et al. [16] found that women are more likely to suffer from postviral olfactory dysfunction in infections caused by parainfluenza, Epstein-Barr virus or human rhinovirus. The similar findings in SARS-CoV-2 infection were obtained from our data.

Consistent with previous reports [17, 18] , a significant negative correlation, although weak (r 2 =0.1250, Figure 2A) , was noticed between viral load and days after symptom onset. The tendency suggests that the viral load is high at the initial stage of SARS-CoV-2 infection, and then gradually decreases after admission. SARS-CoV took nearly 10 days after symptom onset until peak virus load [19] . High initial virus load in COVID-19 patients suggested that SARS-CoV-2 can be transmitted earlier and easier than SARS-CoV. The viral load was reduced rapidly after admission, but could rebound within 2-4 weeks (i.e., day 11, 20, 21, 23, 25 after symptom onset) (Figure 2A) , and a similar rebound pattern was noticed by Huang et al. [18] and by Xu et al. [20] . The antivirals can act effectively on upper respiratory tract and most of lower respiratory tract, but bronchioli terminals could be hardly affected. The coronavirus particles in bronchioli terminals, as well as the virus resistance, may result in the viral rebound in the later course of treatment.

The present study noted no significant difference in Ct values between patients with and without neurosensory dysfunction ( Figure 2B ). Lechien et al. [21] reported that the viral load was significantly higher in patients with olfactory dysfunction duration <12 days compared with those with duration >12 days. They suggest that it is beneficial to perform diagnostic swabs in the first 12 days of olfactory dysfunction to avoid the risk of a false-negative result. Our data may support these findings, with the fact that the viral load is gradually reduced under treatment after admission. Neither gender ( Figure   2D ) nor comorbidity ( Figure 2E ) was noticed to have significant effect on viral load.

These findings are consistent with the report by Huang et al. [18] and the report by To et al. [17] . To et al. [17] reported a positive correlation between age and peak viral load.

However, in this study, no difference in Ct values was noticed between age groups ( Figure 2C ). This inconsistency may be due to that patients in our cohort are much younger (median 25.5 vs 62 years old) and with only one severe COVID-19.

This study has both strengths and limitations. Its major strength is the use of chronological analysis method to detailly present the exact time of onset and duration of neurosensory dysfunction. This study proves that neurosensory dysfunction could be used as a biomarker for early diagnosis of COVID-19. There are two limitations. First, only 86 patients were included. It would be better to conduct a multicenter research with large sample size. Besides, for patients' comfort, we did not use nasopharyngeal swabs, which could be better for assessment of viral load on olfactory mucosa.

In conclusion, the present study detailly provided the exact time of onset and duration of neurosensory dysfunction, and reported the viral load of hospitalized patients with COVID-19. Our findings suggest that the neurosensory dysfunction can be used as a diagnostic marker of early COVID-19, and should be added to the routine screening list for COVID-19.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Construction.

This study is performed in accordance to the principles of the Declaration of Helsinki 

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We declare no conflicts of interest.

